Unlike most carcinomas, breast cancer can recur years after its initial diagnosis. The mechanisms of dormancy, or tumor latency, are unknown. We have found that many breast cancers exhibit a marked reduction in their proliferation rate when they metastasize to lymph nodes. We hypothesize that nodal metastases may survive as quiescent tumor deposits, which are resistant to chemotherapy, and capable of spawning aggressive recurrences many years after the resection of the primary lesion. One explanation may be that breast tumors are dependent on the presence of growth factors found within the breast but absent in lymph nodes. Late recurrences may represent the development of growth factor independence and/or migration to new growth factor rich areas (e.g., liver or bone marrow). Our proposal seeks to determine the role of proliferation rates and growth factors in the unusual natural history of breast cancer, both as prognostic factors and as potential therapeutic targets. In Aim I, we will develop large (>300 patients) cohorts of breast cancer patients and analyze them using a newly developed tissue microarray technique. These cohorts will include matched sets of tissue from both primary lesions and nodal metastases. We will examine proliferation rates and correlate them with growth factor expression and growth factor receptor activation. In Aim II, we will use freshly isolated tissue to determine the amount of growth factor present in primary and nodal metastases. Aim III will analyze the responses of primary human breast tumors to exogenous growth factors, concentrating both on proliferation as well as other downstream markers of tumor activation. Results from all aims will be correlated with patient survival and recurrence rates. The principal investigator in this study is Robert L. Camp, M.D., Ph.D., who has recently completed his residency in pathology at Yale New Haven Hospital. Dr. Camp is interested in pursuing a career in translational research, concentrating on better tools for the diagnosis of cancer and the development of techniques to determine the appropriate treatment for individual tumors. The mentor for this proposal is David Rimm, M.D., Ph.D., who is an established researcher and cytopathologist in the Department of Pathology at Yale U n iversity. Dr. Rimm has an established career in both basic and translational research. The proposed research site, the Department of Pathology, has both the intellectual and physical resources to support Dr. Camp's research, and contains both top quality investigators and "state-of- the-art" core facilities.